The long-term objectives are to identify the biological causes of myopia (near-sightedness) and hyperopia (far-sightedness), and thereby to develop rational means for preventing or treating these conditions. This can be accomplished by investigating the biological mechanisms that control normal ocular growth and refractive development, producing a proper matching of ocular size and focus (emmetropia). The specific aims of this proposal are (1) to further identify, characterize, and test the function of neural circuits in the chick retina that have been proposed to prevent depravation myopia and compensate for positive defocus; (2) to identify neural circuits in the chick retina that compensate for negative defocus; and (3) to identify neural circuits responsible for these or similar functions in retinas of mammals including primates. The research design and methods will be (1) to detect retinal neurons that may control ocular growth and refractive development, by induction of activity markers with visual stimulus conditions known to modify eye growth; (2) to identify the cells in which these markers are induced, and other neurons with which they form synaptic circuits, using light- and electron-microscopical single and double immuno-cytochemical labelling; (3) to test whether these candidate regulatory neurons do in fact control growth and refraction using conventional pharmacological agents and antisense oligodeoxynucleotides to alter the expression or action of intracellular regulatory molecules and intercellular messengers; (4) to use the convenient and productive chick models, to explore a wide range of phenomena and strategies and learn some ways by which retinal activity could regulate growth and refraction; and (5) to extend these strategies and methods to investigate whether the same or similar retinal mechanisms regulate growth and refraction in tree shrews and marmoset monkeys, two important mammalian models. The anticipated outcome is that, for the first time, retinal regulatory neurons and circuits responsible for emmetropization, myopia and hyperopia will be identified conclusively in experimental animal models. The significance is that this new knowledge of cellular and intercellular regulatory messengers will suggest novel molecular targets for preventing refractive disorders, especially those that seriously threaten sight.